Synthesis and Antiproliferative Activity of Cisplatin-3-Chloropiperidine Conjugates.

We report the synthesis and characterization of two novel cisplatin- alkylating agents conjugates. Combining a platinum based cytostatic agent with a sterically demanding alkylating agent could potentially induce further DNA damage, block cell repair mechanisms and keep the substrate active against resistant tumor cell lines. The 3-chloropiperidines utilized as ligands in this work are cyclic representatives of the N-mustard family and were not able to coordinate platinum on their own.

Investigating the anticancer potential of 4-phenylthiazole derived Ru(II) and Os(II) metalacycles.

In this contribution we report the synthesis, characterization and anticancer activity of novel cyclometalated 4-phenylthiazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) complexes. Formation and sufficient purity of the complexes were unambigiously confirmed by H-, C- and 2D-NMR techniques, X-ray diffractometry, HRMS and elemental analysis. The binding preferences of these cyclometalates to selected amino acids and to DNA models including G-quadruplex structures were analyzed.

Interaction with Ribosomal Proteins Accompanies Stress Induction of the Anticancer Metallodrug BOLD-100/KP1339 in the Endoplasmic Reticulum.

The ruthenium-based anticancer agent BOLD-100/KP1339 has shown promising results in several in vitro and in vivo tumour models as well as in early clinical trials. However, its mode of action remains to be fully elucidated. Recent evidence identified stress induction in the endoplasmic reticulum (ER) and concomitant down-modulation of HSPA5 (GRP78) as key drug effects.

Synthesis, Modification, and Biological Evaluation of a Library of Novel Water-Soluble Thiopyridone-Based Organometallic Complexes and Their Unexpected (Biological) Behavior.

A series of 16 dinuclear thiopyridone-based organometallics with excellent water solubility, increased stability and remarkable cytotoxicity were synthesized and characterized. The complexes of this work formed dimeric species featuring a double positive charge in polar protic solvents, accounting for their outstanding solubility in aqueous solution. Most of them displayed higher antiproliferative activity than their parental thiomaltol complex, with unexpected cytotoxicity trends depending on the employed metal center, ligand modification, and cell line.

{Ru(CO)}-Core complexes with benzimidazole ligands: synthesis, X-ray structure and evaluation of anticancer activity in vivo.

The reaction of [Ru(CO)Cl], 1, with N[combining low line]-methylbenzimidazole (MBI) and 5,6-dimethylbenzimidazole (DMBI) afforded two new complexes with the general formula fac-[Ru(CO)ClL], L = MBI (2) or DMBI (4). Crystals of cis,trans-[Ru(CO)Cl(N[combining low line]-MBI)], 3, were also obtained from the mother liquor that produced 2. In the presence of water, the dissociation of Ru-N, Ru-Cl and Ru-CO bonds occurred as a function of time, water content and pH.

Target profiling of an antimetastatic RAPTA agent by chemical proteomics: relevance to the mode of action.

The clinical development of anticancer metallodrugs is often hindered by the elusive nature of their molecular targets. To identify the molecular targets of an antimetastatic ruthenium organometallic complex based on 1,3,5-triaza-7-phosphaadamantane (RAPTA), we employed a chemical proteomic approach. The approach combines the design of an affinity probe featuring the pharmacophore with mass-spectrometry-based analysis of interacting proteins found in cancer cell lysates.

NanoSIMS combined with fluorescence microscopy as a tool for subcellular imaging of isotopically labeled platinum-based anticancer drugs.

Multi-elemental, isotope selective nano-scale secondary ion mass spectrometry (NanoSIMS) combined with confocal laser-scanning microscopy was used to characterize the subcellular distribution of N-labeled cisplatin in human colon cancer cells. These analyses indicated predominant cisplatin colocalisation with sulfur-rich structures in both the nucleus and cytoplasm. Furthermore, colocalisation of platinum with phosphorus-rich chromatin regions was observed, which is consistent with its binding affinity to DNA as the generally accepted crucial target of the drug.

Am(m)ines make the difference: organoruthenium am(m)ine complexes and their chemistry in anticancer drug development.

With the aim of systematically studying fundamental structure-activity relationships as a basis for the development of Ru(II) arene complexes (arene = p-cymene or biphenyl) bearing mono-, bi-, or tridentate am(m)ine ligands as anticancer agents, a series of ammine, ethylenediamine, and diethylenetriamine complexes were prepared by different synthetic routes. Especially the synthesis of mono-, di-, and triammine complexes was found to be highly dependent on the reaction conditions, such as stoichiometry, temperature, and time. Hydrolysis and protein-binding studies were performed to determine the reactivity of the compounds, and only those containing chlorido ligands undergo aquation or form protein adducts.

Novel oximato-bridged platinum(II) di- and trimer(s): synthetic, structural, and in vitro anticancer activity studies.

Novel platinum complexes of trans geometry [PtCl(2){(Z)-R(H)C═NOH}(2)] [R = Me (1), Et (3)] and [PtCl(2){(E)-R(H)C═NOH}{(Z)-R(H)C═NOH}] [R = Me (2), Et (4)] as well as the classic trans-[PtCl(2)(R(2)C═NOH)(2)] [R = Me, Et] were reacted with an equivalent amount of silver acetate in acetone solution at ambient temperature, resulting in formation of unprecedented head-to-tail-oriented oximato-bridged dimers [PtCl{μ-(Z)-R(H)C═NO}{(Z)-R(H)C═NOH}](2) [R = Me (5), Et (7)], [PtCl{μ-(Z)-R(H)C═NO}{(E)-R(H)C═NOH}](2) [R = Me (6), Et (8)], and [PtCl(μ-R(2)C═NO)(R(2)C═NOH)](2) [R = Me (9), Et (10)], correspondingly. The dimeric species feature a unique six-membered diplatinacycle and represent the first example of oxime ligands coordinated to platinum via the oxygen atom. All complexes were characterized by elemental analyses, electrospray ionization mass spectrometry, IR and multinuclear ((1)H, (13)C, and (195)Pt) NMR spectroscopy, as well as X-ray diffraction in the cases of dimers 6 and 9.

Synthesis, characterization, and cytotoxic activity of novel potentially pH-sensitive nonclassical platinum(II) complexes featuring 1,3-dihydroxyacetone oxime ligands.

The reaction of 1,3-dihydroxyacetone oxime with diam(m)minediaquaplatinum(II) under basic conditions produced zwitterionic diam(m)mine(3-hydroxy-2-(oxidoimino)propan-1-olato-κ(2)N,O)platinum(II) complexes featuring the N,O-chelating ligand. Upon reaction with hydrochloric acid, it was possible to isolate either the singly protonated species still exhibiting the intact N,O-chelate or the open-chain chlorido complex. All complexes were characterized in detail with multinuclear ((1)H, (13)C, and (195)Pt) NMR spectroscopy, ESI mass spectrometry, and in one case X-ray diffraction.

Synthesis and characterization of novel bis(carboxylato)dichloridobis(ethylamine)platinum(IV) complexes with higher cytotoxicity than cisplatin.

A series of six novel bis(carboxylato)dichloridobis(ethylamine)platinum(IV) complexes was synthesized and characterized in detail by elemental analysis, FT-IR, ESI-MS, HPLC, multinuclear ((1)H, (13)C, (15)N, (195)Pt) NMR spectroscopy and in one case by X-ray diffraction. Cytotoxic properties of the complexes were evaluated in four human tumor cell lines originating from ovarian carcinoma (CH1 and SK-OV-3), colon carcinoma (SW480) and non-small cell lung cancer (A549) by means of the MTT colorimetrical assay. In addition, their octanol/water partition coefficients (log P values) were determined.